ASCO: AstraZeneca guns for wider ovarian cancer market with Imfinzi-Lynparza combo. Will the FDA buy the plan?

Lynparza may be the most popular PARP inhibitor, but a use restriction in ovarian cancer has been a thorn in AstraZeneca’s side. Now, the British pharma is bringing on its immunotherapy Imfinzi in the hope to remove that thorn, even though the path to market may be thorny.

Adding Lynparza and Imfinzi to standard treatment of chemotherapy and Avastin lowered the risk of progression or death by 37% in newly diagnosed patients with ovarian cancer without BRCA mutations, according to phase 3 data unveiled at the 2023 American Society of Clinical Oncology (ASCO) annual meeting.

Despite the statistically significant win, the lack of evidence for contribution from Imfinzi, a regulatory concern over the use of PARP inhibitors outside BRCA-mutant tumors, and the sheer number of ingredients included in this multidrug regimen could make it hard for AstraZeneca to win over the FDA or gain traction in the clinic.

Meanwhile, AstraZeneca appears to be shifting its focus to longer-term data for its regulatory bid.

“We will share the data with the regulators. Again, [this is an] interim analysis, still immature—we got to still get to the final” progression-free survival [PFS] data, Mohit Manrao, AZ’s U.S. oncology head, sad in an interview with Fierce Pharma.

For now, the DUO-O trial has only accrued less than 20% of the progression or death events for a final PFS analysis, Manrao said.

PARP inhibitors like Lynparza have changed care for patients with BRCA mutations and in the broader HRD-positive population. And there’s a rationale to combine PD-1/L1 inhibitor with a PARP inhibitor, Carlos Doti, M.D., AZ’s head of medical affairs in the U.S. oncology business unit, said in a separate interview.

“Will this be the final combination to solve the problems? I cannot tell you that because it’s too early to say,” Doti said of the DUO-O regimen. “What I can tell you is that we see some positive results in an interim analysis. We need to wait as the data mature, and then we can discuss more."

Before the current readout from the DUO-O trial, Lynparza monotherapy is approved by the FDA as a maintenance therapy in BRCA-mutant ovarian cancer after response to first-line chemo. And the Lynparza-Avastin pairing is allowed in a broader population with any kind of homologous recombination deficiency (HRD) mutations. Now, for DUO-O, AZ is proposing adding Imfinzi to chemo upfront, followed by Imfinzi and Lynparza as maintenance.

First, what role Imfinzi plays in the combo “requires further investigation,” Carol Aghajanian, M.D., from the Memorial Sloan Kettering Cancer Center and an investigator of DUO-O, said in a press briefing ahead of the presentation at ASCO’s annual meeting in Chicago. 

The trial appeared to have proven Lynparza’s worth. In another arm of the DUO-O trial, the addition of Imfinzi—without Lynparza—only lowered the risk of disease progression or death by 13%, which wasn’t statistically significant.

However, it’s not clear if Lynparza alone is enough because there isn’t a separate arm testing that regimen without Imfinzi. The Imfinzi-Lynparza combo’s 37% PFS benefit did appear better than the 29% shown by Lynparza in the PAOLA-1 trial in a similar population. But such cross-trial comparisons are problematic because of different patient characteristics.

To make things worse, two other PD-L1 inhibitors also failed in front-line ovarian cancer, including Roche’s regimen of Tecentriq, Avastin and chemo.

With the addition of Imfinzi, AZ’s main goal is to reach the roughly 50% of HRD-negative population, a group that’s proven harder for PARP inhibitors to tackle. But the new regimen’s performance was weaker in those patients.

In the DUO-O trial, about 37% of patients between the Imfinzi-Lynparza arm and control group have other non-BRCA HRD mutations. Among those HRD-positive patients, the Imfinzi-Lynparza pairing pulled off a larger, 51% edge in progression-free survival. This means the benefit in HRD-negative patients came below the 37% in the overall population, although Aghajanian said it’s still “clinically meaningful.”

The weaker HRD-negative data could become an obstacle for AZ as it targets a broad population. The FDA has recently cracked down on the PARP inhibitor class in non-BRCA patients. The FDA on Thursday just approved Lynparza, used in tandem with Johnson & Johnson’s Zytiga, for metastatic castration-resistant prostate cancer, but only in BRCA-mutant patients, even though the regimen’s data in all patients were also statistically significant.

That was because the FDA viewed the Lynparza-Zytiga combo’s tumor progression benefit in non-BRCA patients as modest but instead noticed a sign of potential harm to patient survival.

For now, researchers don’t have overall survival data to share from DUO-O, and Aghajanian said those results could take a long time to read out. But she pointed to other PARP inhibitor studies, saying that she feels confident that the PFS benefit could eventually translate into life extensions.

PFS is very important to patients, and the DUO-O regimen represents “progress,” Merry Jennifer Markham, M.D., from the University of Florida, an invited ASCO expert, said during the press briefing.

But even if AZ somehow persuaded the FDA into an approval, the fact that it involves so many drugs might pose an access problem.

Markham said she’s “less optimistic” about access to the DUO-O regimen. Besides benefit, the “financial toxicity that individual patient may experience” will also be part of her discussion with patients, Markham said.

Editor's Note: The story has been updated on June 5 with additional comments from AstraZeneca's Mohit Manrao and Carlos Doti.

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